Natural proteome diversity links aneuploidy tolerance to protein turnover
Open accessPublished version of a preprint
Abstract
Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy—an imbalance in chromosome copy numbers—is frequent 1,2 (around 20%), which seems to contradict the substantial fitness costs and transient nature of aneuploidy when it is engineered in the laboratory 3–5 . Here we generate a proteomic resource and merge it with genomic 1 and transcriptomic 6 data for 796 euploid and aneuploid natural isolates. We find that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins—especially subunits of protein complexes—show reduced expression, but the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage compensated, and average protein levels are shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and shows the utility of exploiting the natural diversity of species to attain generalizable molecular insights into complex biological processes.
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- Authors
- Muenzner, J., Trébulle, P., Agostini, F., Zauber, H., Messner, C. B., Steger, M., Kilian, C., Lau, K., Barthel, N., Lehmann, A., Textoris-Taube, K., Caudal, E., Egger, A.-S., Amari, F., De Chiara, M., Demichev, V., Gossmann, T. I., Mülleder, M., Liti, G., Schacherer, J., Selbach, M., Berman, J., & Ralser, M.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Centre for Human Genetics (GB)
- Max Delbrück Center (DE)
- University of Zurich (CH)
- Evotec (Germany) (DE)
- The Francis Crick Institute (GB)
- TU Dortmund University (DE)
- Centre National de la Recherche Scientifique (FR)
- Tel Aviv University (IL)
- Corresponding author
- Berman, Judith
- Ralser, Markus
- ORCID
- Venue
- Nature
- Published
- 2024-05-22
- Volume
- 630
- Issue
- 8015
- Pages
- 149-157
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11153158
- OpenAlex
- W4398201077
- Cited by
- 81
- References
- 11
- Citations by year
- 2026: 17 · 2025: 30 · 2024: 17 · 2023: 12 · 2022: 5
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (FC001134, 200829/Z/16/Z)
- Francis Crick Institute (10134, FC001134)
- Cancer Research UK (FC001134)
- European Commission (HORIZON2020)
- Agence Nationale de la Recherche (-15-IDEX-01, ANR‐15‐IDEX‐01)
- Bundesministerium für Bildung und Forschung (031L0220)
- Medical Research Council (FC001134)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- aneuploidy tolerance, protein turnover, Saccharomyces cerevisiae, natural genetic variation, proteome, dosage compensation, gene dosage, proteasome, ubiquitination, attenuation, wild isolate
- MeSH terms
- Aneuploidy, Dosage Compensation, Genetic, Saccharomyces cerevisiae, Genetic Variation, Proteome, Gene Expression Profiling, Genomics, Saccharomyces cerevisiae Proteins, Proteomics, Proteasome Endopeptidase Complex, Ubiquitination, Proteolysis
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